TY - JOUR
T1 - Working memory deficits in neuronal nitric oxide synthase knockout mice
T2 - Potential impairments in prefrontal cortex mediated cognitive function
AU - Zoubovsky, Sandra P.
AU - Pogorelov, Vladimir M.
AU - Taniguchi, Yu
AU - Kim, Sun Hong
AU - Yoon, Peter
AU - Nwulia, Evaristus
AU - Sawa, Akira
AU - Pletnikov, Mikhail V.
AU - Kamiya, Atsushi
N1 - Funding Information:
We thank Dr. Solomon H. Snyder for providing nNOS KO mice. We thank Drs. Michela Gallagher, Dani R. Smith, Hanna Jaaro-Peled, and Minae Niwa for valuable discussions and Ms. Yukiko Lema for organizing the manuscript. This work was supported by grants from MH-091230 (A.K.), MH-083728 (M.P.), Silvio Conte Center grants MH-084018 (A.S.), and foundation grants from NARSAD (A.K., M.P., A.S.), and S-R (A.K., A.S.).
PY - 2011/5/20
Y1 - 2011/5/20
N2 - Neuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-Schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning.
AB - Neuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-Schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning.
KW - Cognition
KW - DISC1
KW - NNOS
KW - Prefrontal cortex
KW - Schizophrenia
KW - Working memory
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U2 - 10.1016/j.bbrc.2011.04.097
DO - 10.1016/j.bbrc.2011.04.097
M3 - Article
C2 - 21539806
AN - SCOPUS:79956223279
SN - 0006-291X
VL - 408
SP - 707
EP - 712
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -